CN1446225A - 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, method of preparing same, and anticancer composition comprising same as active ingredients - Google Patents
5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, method of preparing same, and anticancer composition comprising same as active ingredients Download PDFInfo
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Abstract
Disclosed is a new fluorocytosine and derivatives thereof. The fluorocytosine and derivatives thereof provide a pharmaceutical composition exhibiting better anti-cancer characteristics than the conventional composition.
Description
Technical field
The present invention relates to 5 '-'-deoxy-n-(replacing the oxygen carbonyl)-5-flurocytosine and derivative, preparation method and comprise the anti-cancer composition of this material as activeconstituents.More particularly, the present invention relates to show good anticancer active 5 '-'-deoxy-n-(replacing the oxygen carbonyl)-5-flurocytosine and derivative thereof, preparation method, and relate to and comprise the anti-cancer composition of this material as activeconstituents.
Background technology
Cancer is one of can not cure diseases, and these diseases become the problem that will solve with acquired immune deficiency syndrome (AIDS) (AIDS) in the modern medical service science.Dissimilar and the number of cases of cancer increases year by year at home and its low curative ratio causes many people's death.Even carried out many cancer researches, but also do not develop suitable medicine.Therefore, require exploitation to have good efficiencies and the cancer therapy drug of being free from side effects more effectively to cure cancer.
At present, topical therapeutic such as surgical operation or radiotherapy, or systematic treating is just being attempted using to cure cancer as adopting chemical or immunotherapy.In these treatments, chemotherapy is widely used in and increases the topical therapeutic program, or is used for the treatment of the tumor that takes place as main canceration in various internals such as stomach, liver or lung, is used for various hematologic cancers equally or is used to reduce cancer metastasis.
The research that is used for chemotherapeutic cancer therapy drug is being attempted actively developing various carcinostatic agents such as 5 FU 5 fluorouracil (5-FU), methotrexate, frutraful and cis-platinum, and recently also in the research of carrying out novel cancer therapy drug.Yet, also do not develop fully and stably cure the cancer therapy drug of cancer.
Recently, used the research of 5-FU cancer therapy drug, 5-FU is a kind of candidate of pyrimidine neucleoside cancer therapy drug.5-FU is synthetic curing the material of cancer by what prevent pyrimidine and neucleotide, but it is toxic to stomach and intestines, and it has severe side effect.Therefore, the research with the 5-FU derivative that reduces side effect is enlivened, but new 5-FU derivative has the side effect that causes diarrhoea by activation 5-FU derivative in the intestines wall still after oral administration.
Recently, developed the N of general formula 1
4-alkoxy carbonyl-5-flurocytosine derivative, it is by the enzyme activation in lung rather than in intestines and can reduce side effect (European patent No.6,025,454, unsettled open No.94-211891 of Japanese Patent and U.S. patent No.5,472,949).
Wherein, R
aIt is saturated or unsaturated hydrogen carbonic ether; R
bBe hydrogen, the group of hydrolysis easily or the blocking group of under physiological condition, removing easily.
Yet the shortcoming of derivative is that antitumour activity is lower to a certain extent.Therefore, need exploitation to show good anticancer active new anti-cancer drug thing.
Summary of the invention
The purpose of this invention is to provide and show good anticancer active 5 '-'-deoxy-n-replacement oxygen carbonyl-5-flurocytosine and derivative thereof.
Another object of the present invention provides the preparation method of 5 '-'-deoxy-n-replacement oxygen carbonyl-5-flurocytosine and derivative thereof.
The present invention's another purpose in addition provides and comprises 5 '-'-deoxy-n-replacement oxygen carbonyl-5-flurocytosine, and or derivatives thereof is as the anti-cancer composition of activeconstituents.
These and other objects can be reached by 5 '-'-deoxy-n-replacement oxygen carbonyl-5-flurocytosine and derivative, pharmaceutical salts or the solvation material of general formula 2 or 3.
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
Embodiment
The compounds that the present invention relates to have good antitumour activity and can be used for cancer therapy drug, and provide and have general formula 2 or 3 and 5 '-'-deoxy-n of derivative-(replacing the oxygen carbonyl)-5-flurocytosine and derivative thereof, and pharmaceutical salts or solvation material.
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily, preferred hydrogen or ethanoyl; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
Illustrate in greater detail the preparation of the 5-flurocytosine compound of general formula 2 of the present invention or 3 with reference to following reaction formula 1.
＜reaction formula 1 〉
Wherein, R
1Be hydrogen, C
1-C
7Alkyl or C
1-C
7Thiazolinyl; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl.
In the presence of solvent such as acetonitrile, add suitable additive, as titanium chloride (IV), iodine trimethyl silane or chlorine trimethyl silane/sodium iodide, β-D-the ribofuranose 1,2,3 that mixes general formula 6, the trimethyl silicone hydride 5-flurocytosine of 5-tetraacetate and general formula 7 is with the compound of preparation general formula 4.
, under solvent such as methylene dichloride or pyridine, add suitable alkali, as pyridine, triethylamine or diisopropylethylamine, with the compound of compound (Korean application No.2000-46179) Yu the general formula 5 of general formula 4, with the compound of preparation general formula 3b thereafter.
Alcohol as methyl alcohol or ethanol in the presence of, the use C
1-C
2Sodium alkoxide or sodium hydroxide, the compound of reduction general formula 3b is to obtain the compound of general formula 3a.
Use appropriate catalyst under room temperature-120 ℃, the compound of reaction expression 3a and oxygen are with the purpose compound of acquisition general formula 2a of the present invention.
Perhaps, the compound that shakes general formula 2a simultaneously drips C under-30 ℃～room temperature
1-C
7Alkyl alcohol or alkenyl alcohol and Thionyl difluoride are to obtain the ester derivative compound of general formula 2b.
The present invention relates to comprise the anti-cancer composition of 5 '-'-deoxy-n-(replacing the oxygen carbonyl)-5-flurocytosine derivative as activeconstituents.Composition of the present invention can be differently to the oral or non-oral administration of patient, and composition can comprise compound, pharmaceutical salts or the solvation material of general formula 2 or 3.Anti-cancer composition of the present invention also can comprise physiology acceptable liquid or solid carrier.
But the solid preparation form can comprise powder, tablet dispersed particle or capsule; The suitable drugs in solid type that is used for oral administration can be tablet, powder or capsule.Suitable carriers can be thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent and/or refining swelling agent.If use powder or capsule preparations form, carrier can comprise seed activity composition 5-70%, preferred 10-70%.Suitable solid carrier or vehicle can be W-Gum, Magnesium Stearate, film, polyoxyethylene glycol, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, Vltra tears, methylcellulose gum, Xylo-Mucine, titanium dioxide, have low-melting wax, cocoa powder or butter.
Liquid preparation can be solution, suspension or emulsion.For example, non-oral injection solution comprises water or blended water-propylene glycol, and injection has suitable isotonicity energy and the pH that is used for body system.Liquid preparation also can be the polyoxyethylene glycol aqueous solution.Can pass through lytic activity composition in water, and add flavouring agent, tinting material, stablizer and concentrated assistant in the material that obtains, preparation is used for the suitable aqueous solution of oral administration.Can prepare the suitable water suspending agent that contains that is used for oral administration in viscosity material such as natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or the conventional suspension agent by the particle activeconstituents is joined.
Preferred drug substances is a unit administration type.Preparation comprises the activeconstituents that separates appropriate amount in the administration unit, and wherein each administration unit can be packaged as the preparation of fractional dose, for example, in bottle or a large amount of, tablet, capsule or as powder.
Further be explained in more detail the present invention with reference to following embodiment, but embodiment is not limited to the present invention.
Embodiment 1:
2 ', 3 ', 5 '-three-O-ethanoyl-N
4-propargyl oxygen carbonyl-5-flurocytosine (R
3=propargyl, the compound of general formula 3b) preparation:
150ml methylene dichloride and 9ml pyridine are joined 2 ', 3 ' of 18.1g, in 5 '-three-O-ethanoyl-5-flurocytosine, under 0 ℃,, at room temperature shook subsequently 30 minutes to wherein adding 8.0g chloroformic acid alkynes propyl ester.In the material that obtains, add sodium bicarbonate aqueous solution, the material that obtains is adopted the 300ml dichloromethane extraction three times, dry under anhydrous magnesium sulfate subsequently, and filter.The product vapourisation under reduced pressure that obtain to be concentrated and it is by silica gel column chromatography refining, obtained 21.9g title product (yield 88%) thereafter.
1H?NMR(CDCl
3，ppm)δ11.45(br.s，1H)，8.20(t，1H)，6.01(s，
1H)，5.43(m，1H)，5.26(m，1H)，4.79(dd，2H)，4.42(m，1H)，4.36(m，
2H)，2.52(t，1H)，2.10(s，3H)，2.01(s，3H)
Embodiment 2:
N
4-(propargyl oxygen carbonyl)-5-flurocytosine (R
3=propargyl, the compound of general formula 3a) preparation:
With 2 ', 3 ' of 19.1g, 5 '-three-O-ethanoyl-N
4-propazyl oxygen carbonyl-5-flurocytosine adds and is dissolved in 150ml methyl alcohol.The 1N sodium methylate of 150ml is joined in the material of acquisition, it was shaken 1 hour, adopt the neutralization of 1N hydrochloric acid, vapourisation under reduced pressure is to concentrate it subsequently.100ml water is joined in the acquisition thing, its is adopted methylene chloride (95: 5) solution extraction several times, by anhydrous magnesium sulfate drying, filtration and vapourisation under reduced pressure are to concentrate it.Use ethyl acetate recrystallize spissated material to obtain 12.3g title product (yield: 80%) thereafter.
1H?NMR(CD
30D，ppm)δ8.15(d，1H)，5.93(d，1H)，4.77(d，2H)，
4.11(m，1H)，3.95(m，1H)，3.72(m，3H)，2.50(t，1H)
Embodiment 3:
5 '-'-deoxy-n
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=propargyl, the compound of general formula 2a) preparation:
The 600ml sodium bicarbonate buffer solution of pH8-10 is joined the N of 10.25g
4In-propargyl oxygen carbonyl-5-flurocytosine, to wherein adding platinum-oxide catalyst, oxygen was injected down the material that obtains 12 hours at 90 ℃, it is filtered to remove catalyzer, adopt methylene chloride (95: 5) solution extraction several times, by anhydrous magnesium sulfate drying, vapourisation under reduced pressure uses the ethyl acetate recrystallize to obtain 6.50g title product (yield 66%) it to concentrate it.
1H?NMR(CD
3OD，ppm)δ10.43(br.s，1H)，8.01(br.s，1H)，5.75
(d，1H)，4.95(d，1H)，4.80(d，2H)，4.63(m，1H)，4.28(m，1H)，2.55(t，
1H)
Embodiment 4:
Ethyl-5 '-'-deoxy-n
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylicesters (R
1=ethyl, R
3=propargyl, the compound of general formula 2b) preparation:
100ml ethanol is joined 5 ' of 1.0g-'-deoxy-n
4In-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid, under-30 ℃～0 ℃ temperature,, it was at room temperature shaken 6-12 hour, filter, adopt washing with alcohol and vapourisation under reduced pressure to concentrate it to wherein dripping the 0.6ml thionyl chloride.Sodium bicarbonate aqueous solution is joined in the material of acquisition with precipitated solid, solid is adopted water and washing with alcohol, and dry to obtain 1.21g title product (yield 88%).
1H?NMR(CDCl
3，ppm)δ10.35(br.s，1H)，8.01(br.s，1H)，5.77(d，
1H)，4.88(d，1H)，4.81(d，1H)，4.29(m，2H)，4.12(q，2H)，2.50(t，1H)，
1.24(t，3H)
Embodiment 5:
5 '-'-deoxy-n
4The evaluation of the external antitumour activity of-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (general formula 2a) derivative:
For using 5-FU to measure 5 '-'-deoxy-n as the reference compound
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=propargyl, 2a compound) external antitumour activity is estimated the cytotoxicity to the human cancer cell.The cancer cells that uses is A549 (lung cancer), HCT15 (colorectal carcinoma), SK-OV-3 (ovarian cancer) and SK-MEL-2 (melanoma cancer).
With cancer cells in having the brooder of constant humidity, at 37 ℃ and 5%CO
2Under hatch, use RPMI medium to be used for media base with additional 10% fetal bovine serum.Be recognizing cells toxicity, will be in 2-5 * 10 of the cancer cells of logarithm in mutually at 96 pond plates
4Each pond of individual cell is inoculation down, and hatches 24 hours.With 5-FU and 5 '-'-deoxy-n
4The sample solution of-propargyl oxygen carbonyl-5-flurocytosine-5 '-carboxylic acid progressively joins the pond neutralization and hatched 72 hours.The 5mg/ml MTT reaction soln that will be dissolved in 20 μ l of normal saline solution joins in the pond of hatching plate and hatched 4 hours.The first moon that produces is dissolved in methyl-sulphoxide for crystal and measures the number of the light absorption ratio in each pond with the calculating viable cell under 540nm.Medium will be arranged and do not have the pond light absorption ratio of cell to be set at 0%, will not have the pond light absorption ratio of sample to be set at 100%, the concentration corresponding to 50% is called IC
50(μ g/ml) value.The results are shown in Table 1.
| Concentration (μ g/ml) | A549 | ?SK-OV-3 | ?HCT15 | ?SK-MEL2 |
| 5-FU | 0.26 | ?0.03 | ?0.11 | ?0.63 |
| Embodiment 3 compounds | 0.005 | ?0.005 | ?0.040 | ?0.007 |
Table 1
As shown in table 1, the compound of general formula 3 is to the antitumour activity of the about 0.04-0.07 μ g/ml of each cancer cells demonstration, and comparing it with contrast is excellent.
Embodiment 6:
5 '-'-deoxy-n
4The evaluation of the external antitumour activity of-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (general formula 2a) derivative:
Has good anticancer active capecitabine (5 '-'-deoxy-n in disclosed 5 '-'-deoxy-n in European patent No.602454-alkyl oxygen carbonyl-5-flurocytosine derivative
4-(amyl group oxygen carbonyl)-5-flurocytosine (in general formula 1, R
a=amyl group, R
b=hydrogen)) as reference compound, from 5 '-'-deoxy-n of embodiment 3 acquisitions
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (general formula 2a) is measured the antitumour activity to mouse tumor cell line L1210 as sample.
The mouse of using is big BDF1 male mouses (19-20g) of 5 weeks, and these mouse adapted to for 1 week available from Charles RiverJapan with these mouse.With the breeding condition enactment of mouse is 24 ± 2 ℃ temperature and 50 ± 1 ℃ humidity.Purifying waste water of will being used to drink biweekly offers mouse, and straw and one week of cage are changed once.Use every group of two mouse to test.As tumor cell line, use L1210 mouse blood tumor cell system, and, adopt inferior phosphorus buffered soln (pH7.2) washing clone twice or three times of subculture in the Falcon culturing bottle, at microscopically quantitatively to produce 1 * 10
7The cell suspending liquid of/ml uses 1ml disposable sterilization syringe with 100 (1 * 10
6) ml cell suspending liquid belly injection gives mouse.After Transplanted cells, give 24 hours with drug oral.For mouse separately, the concentration that gives of capecitabine is 1.2,5.7,28.8,144 and 720mg/kg/100 μ l, and for mouse separately, the concentration that gives of general formula 2a compound of the present invention is 1.2,5.8 and 28.8mg/kg/100 μ l.Capecitabine is dissolved in methyl-sulphoxide and in 0.5% carboxymethyl cellulose, suspends, the compound of general formula 2a is dissolved in distilled water.Give mouse one Friday in inferior totally 3 weeks with sample, amount to 15 times, beginning in 24 hours after tumour cell gives.Antitumour activity is measured as increase life-span for contrast.The results are shown in Table 2.
| Compound | Dosage (mg/kg/ days) | The average survival date (my god) | The life-span (%) that increases |
| Contrast | ????- | ????17.8 | ????- |
| Capecitabine | ????720 ????144 ????28.8 ????5.8 | ????22.8 ????20.1 ????20.2 ????19.2 | ????30 ????15 ????14 ????8 |
| The compound of embodiment 3 | ????28.8 ????5.8 ????1.2 | ????21.9 ????20.6 ????20.1 | ????23 ????11 ????8 |
Table 2
As shown in table 2, the compound by animal experiment embodiment 3 shows good anti-cancer activity in vivo.
As mentioned above, N
4-(alkynyloxy carbonyl)-5-flurocytosine and derivative can be used as cancer therapy drug.
Embodiment 7:
2 ', 3 ', the preparation of 5 '-three-O-ethanoyl-5-flurocytosine 4
In the presence of nitrogen, to β-D-ribofuranose 1,2,3 of 6.22g, the trimethyl silicone hydride 5-flurocytosine 7 that adds the 60ml acetonitrile in the 5-tetraacetate 6 and obtain from the 5-flurocytosine of 3.2g.Under-50～0 ℃ to wherein adding 3ml tin chloride (IV), it was at room temperature shaken 4-8 hour, in the material that obtains, add sodium bicarbonate aqueous solution, it is adopted the 100ml ethyl acetate extraction three times, dry under anhydrous magnesium, and filtration and vapourisation under reduced pressure are refining to obtain the title compound thing (yield 81%) of 6.13g general formula 4 by silica gel column chromatography with obtaining thing to concentrate it.
1H?NMR(CDCl
3，ppm)δ7.65(d，1H)，6.09(d，1H)，5.33(dd，1H)，
5.26(dd，1H)，4.35(m，3H)，2.14(s，3H)，2.08(s，3H)，2.06(s，3H)
Embodiment 8:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(propyl group oxygen carbonyl)-cytosine(Cyt) (R
3=propyl group, the compound of general formula 3b) preparation
20ml methylene dichloride and 1.1ml pyridine are joined 2 ', 3 ' of 2.33g, in 5 '-three-O-ethanoyl-5-flurocytosine 4 and under 0 ℃ to wherein dripping 1.01g propyl chloroformate (R
3=propyl group, the compound of general formula 5), it was at room temperature shaken 30 minutes, join in the sodium bicarbonate aqueous solution, adopt the 50ml dichloromethane extraction three times, dry under anhydrous magnesium sulfate, vapourisation under reduced pressure and refining to obtain the title product (yield 90%) of 2.52g general formula 3b by silica gel column chromatography.
1H?NMR(CDCl
3，ppm)δ12.01(br.s，1H)，7.58(br.s，1H)，
6.09(br.s，1H)，5.33(d，1H)，4.44(m，3H)，4.12(t，2H)，2.14(s，3H)，
2.12(s，3H)，2.11(s，3H)，1.61(m，2H)，1.00(t，3H)
Embodiment 9-15:
Prepare compound by program identical among the embodiment 8, difference is to use respectively R
3General formula 5 compounds replacement propyl chloroformate for ethyl, butyl, amyl group, hexyl, heptyl, allyl group and propargyl.
Embodiment 9:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(ethyl oxygen carbonyl)-cytosine(Cyt) (R
3=ethyl, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ12.00(br.s，1H)，7.55(br.s，1H)，6.10(d，
1H)，5.34(m，2H)，4.38(m，3H)，4.15(q，2H)，2.11(s，3H)，2.10(s，3H)，
2.08(s，3H)，1.32(t，3H)
Embodiment 10:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(butyl oxygen carbonyl)-cytosine(Cyt) (R
3=butyl, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ12.04(br.s，1H)，7.54(br.s，1H)，6.11
(br.s，1H)，5.30(m，2H)，4.40(m，3H)，4.14(t，2H)，2.13(s，3H)，2.11(s，
3H)，1.69-1.25(m，4H)，0.90(t，3H)
Embodiment 11:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(amyl group oxygen carbonyl)-cytosine(Cyt) (R
3=amyl group, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ12.01(br.s，1H)，7.61(br.s，1H)，6.06
(br.s，1H)，5.27(m，2H)，4.37(m，3H)，4.12(t，2H)，2.15(s，3H)，2.10(s，
3H)，2.08(s，3H)，1.71-1.31(m，6H)，0.92(t，3H)
Embodiment 12:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(hexyl oxygen carbonyl)-cytosine(Cyt) (R
3=hexyl, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ11.94(br.s，1H)，7.53(d，1H)，6.09(d，
1H)，5.28(m，2H)，4.36(m，3H)，4.13(t，2H)，2.14(s，3H)，2.10(s，3H)，
2.09(s，3H)，1.73-1.25(m，8H)，0.92(t，3H)
Embodiment 13:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(heptyl oxygen carbonyl)-cytosine(Cyt) (R
3=heptyl, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ11.94(br.s，1H)，7.60(d，1H)，5.27(m，
2H)，4.37(m，3H)，4.14(t，2H)，2.15(s，3H)，2.13(s，3H)，2.09(s，3H)，
1.73-1.25(m，10H)，0.92(t，3H)
Embodiment 14:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(allyloxycarbonyl)-cytosine(Cyt) (R
3=allyl group, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ12.00(br.s，1H)，7.63(d，1H)，6.10(d，
1H)，5.89(m，2H)，5.27(m，2H)，4.77(d，2H)，4.39(m，3H)，2.13(s，3H)，
2.12(s，3H)，2.10(s，3H)
Embodiment 15:
2 ', 3 ', 5 '-three-O-ethanoyl-5-fluoro-N
4-(propargyl oxygen carbonyl)-cytosine(Cyt) (R
3=propargyl, the compound of general formula 3b)
1H?NMR(CDCl
3，ppm)δ11.45(br.s，1H)，8.20(t，1H)，6.01(s，
1H)，5.43(m，1H)，5.26(m，1H)，4.79(dd，2H)，4.42(m，1H)，4.36(m，
2H)，2.52(t，1H)，2.10(s，3H)，2.01(s，3H)
Embodiment 16:
5-fluoro-N
4-(amyl group oxygen carbonyl)-cytosine(Cyt) (R
3=amyl group, the compound of general formula 3a) preparation
With 2 ', 3 ' of 6.47g, 5 '-three-O-ethanoyl-5-fluoro-N
4-(amyl group oxygen carbonyl)-cytosine(Cyt) (R
3=amyl group, the compound of general formula 3b) add and be dissolved in the 1N sodium methylate of 50ml methyl alcohol and 50ml, it was shaken 1 hour, adopt the neutralization of 1N hydrochloric acid, vapourisation under reduced pressure is to concentrate it subsequently.30ml water is joined wherein, adopt methylene chloride (95/5) solution extraction several times, by the anhydrous magnesium drying, filtration and vapourisation under reduced pressure use the ethyl acetate recrystallize to obtain 4.11g title product (yield 85%) to concentrate.
1H?NMR(CDCl
3，ppm)δ8.00(d，1H)，5.86(br.s.，1H)，1.13(t，
2H)，4.03(m，2H)，3.87(dd，1H)，3.74(dd，1H)，3.55(m，1H)，1.65(m，
2H)，1.36(m，4H)，0.92(t，3H)
Embodiment 17-23:
Prepare compound by program identical among the embodiment 16, difference is to use respectively R
3Be the general formula 3b compound replacement 2 ', 3 ' of ethyl, propyl group, butyl, hexyl, heptyl, allyl group and propargyl, 5 '-three-O-ethanoyl-5-fluoro-N
4-(amyl group oxygen carbonyl)-cytosine(Cyt).
Embodiment 17:
5-fluoro-N
4-(ethyl oxygen carbonyl)-cytosine(Cyt) (R
3=ethyl, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ7.98(d，1H)，5.88(br.s.1H)，4.15(q，
2H)，4.05(m，2H)，3.87(dd，1H)，3.73(dd，1H)，3.56(m，1H)，1.30(t，
3H)
Embodiment 18:
5-fluoro-N
4-(propyl group oxygen carbonyl)-cytosine(Cyt) (R
3=propyl group, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ7.98(br.s，1H)，5.86(br.s，1H)，4.13(t，
2H)，4.01(m，2H)，3.88(m，1H)，3.75(dd，1H)，3.56(m，1H)，1.61(m，
2H)，0.96(t，3H)
Embodiment 19:
5-fluoro-N
4-(butyl oxygen carbonyl)-cytosine(Cyt) (R
3=butyl, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ8.01(d，1H)，5.81(br.s，1H)，4.14(t，
2H)，3.88(m，2H)，3.77(dd，1H)，3.56(m，1H)，1.57-1.33(m，4H)，0.95
(t，3H)
Embodiment 20:
5-fluoro-N
4-(hexyl oxygen carbonyl)-cytosine(Cyt) (R
3=hexyl, the compound of general formula 3a)
1H?NMR?CDCl
3，ppm)δ7.95(d，1H)，5.80(br.s，1H)，4.14(t，2H)，
4.02(m，2H)，3.88(dd，1H)，3.75(dd，1H)，3.55(m，1H)，1.57-1.29(m，
8?H)，0.94(t，3H)
Embodiment 21:
5-fluoro-N
4-(heptyl oxygen carbonyl)-cytosine(Cyt) (R
3=heptyl, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ8.03(d，1H)，5.88(br.s，1H)，4.16(t，
2H)，4.05(m，2H)，3.90(dd，1H)，3.77(dd，1H)，3.56(m，1H)，1.57-1.61
(m，10H)，0.94(t，3H)
Embodiment 22:
5-fluoro-N
4-(allyloxycarbonyl)-cytosine(Cyt) (R
3=allyl group, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ8.05(d，1H)，5.90(ms，2H)，5.26(m，
2H)，4.77(d，2H)，4.09(m，2H)，3.94(dd，1H)，3.78(dd，1H)，3.58(m，
1H)
Embodiment 23:
5-fluoro-N
4-(propargyl oxygen carbonyl)-cytosine(Cyt) (R
3=propargyl, the compound of general formula 3a)
1H?NMR(CDCl
3，ppm)δ8.15(d，1H)，5.93(d，1H)，4.77(d，2H)，
4.11(m，1H)，3.95(m，1H)，3.72(m，3H)，2.50(t，1H)
Embodiment 24:
5 '-'-deoxy-n
4-(hexyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=hexyl, the compound of general formula 2a) preparation
5-fluoro-N with 1.72g
4-(hexyl oxygen carbonyl)-cytosine(Cyt) (R
3=hexyl, the compound of general formula 3a) joins in the 10ml sodium bicarbonate buffer solution of pH8-10, to wherein adding platinum-oxide catalyst, oxygen was injected down the material that obtains 12 hours at 90 ℃, it is filtered to remove catalyzer, adopt methylene chloride (95/5) solution extraction several times, by the anhydrous magnesium drying, filter and vapourisation under reduced pressure, use the ethyl acetate recrystallize to obtain 1.30g title product 2a (yield 71%).
1H?NMR(CDCl
3，ppm)δ8.05(br.s，1H)，5.87(d，1H)，4.55-4.02
(m，5H)，1.60(m，2H)，1.34(m，6H)，0.89(t，3H)
Embodiment 25-31:
Prepare compound by program identical among the embodiment 24, difference is to use respectively R
3General formula 3a compound replacement 5-fluoro-N for ethyl, propyl group, butyl, amyl group, heptyl, allyl group and propargyl
4-(hexyl oxygen carbonyl)-cytosine(Cyt).
Embodiment 25:
5 ,-'-deoxy-n
4-(ethyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=ethyl, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ8.08(br.s，1H)，5.91(d，1H)，4.56-4.05
(m，5H)，1.30(t，3H)
Embodiment 26:
5 '-'-deoxy-n
4-(propyl group oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=propyl group, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ8.06(br.s，1H)，5.89(d，1H)，4.53-4.03
(m，5H)，1.61(m，2H)，0.88(t，3H)
Embodiment 27:
5 '-'-deoxy-n
4-(butyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=butyl, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ8.05(br.s，1H)，5.88(d，1H)，4.53-4.03
(m，5H)，1.57-1.33(m，4H)，0.90(t，3H)
Embodiment 28:
5 '-'-deoxy-n
4-(amyl group oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=amyl group, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ8.05(br.s，1H)，5.86(d，1H)，4.51-4.05
(m，5H)，1.58-1.25(m，6H)，0.90(t，3H)
Embodiment 29:
5 '-'-deoxy-n
4-(heptyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=heptyl, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ8.03(br.s，1H)，5.86(d，1H)，4.53-4.03
(m，5H)，1.60-1.28(m，10H)，0.91(t，3H)
Embodiment 30:
5 '-'-deoxy-n
4-(allyloxycarbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=allyl group, the compound of general formula 2a) preparation
1H?NMR?CDCl
3，ppm)δ8.11(br.s，1H)，5.92(m，2H)，5.22(m，
2H)，1.79(d，2H)，4.56-4.05(m，3H)
Embodiment 31:
5 '-'-deoxy-n
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=propargyl, the compound of general formula 2a) preparation
1H?NMR(CDCl
3，ppm)δ10.43(br.s，1H)，8.01(m，2H)，5，75(d，
1H)，4.95(d，1H)，4.63(m，1H)，4.28(m，1H)，2.55(t，1H)
Embodiment 32:
Ethyl-5 '-'-deoxy-n
4-(hexyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylicesters (R
3=hexyl, the compound of general formula 2a) preparation
With 5 ' of 1.04g-'-deoxy-n
4-(hexyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=hexyl, the compound of general formula 2a) joins in the 100ml methyl alcohol, under-30 ℃～0 ℃ temperature to wherein dripping the 0.6ml thionyl chloride, it was at room temperature shaken 6-12 hour, filter, adopt washing with alcohol, vapourisation under reduced pressure is to concentrate, sodium bicarbonate aqueous solution is joined in the material of acquisition with precipitated solid, solid is adopted water and washing with alcohol and dry to obtain 1.30g title product 2b (yield 92%).
1H?NMR(CDCl
3，ppm)δ8.06(br.s，1H)，5.90(d，1H)，4.55-4.02
(m，7H)，1.64＝1.09(m，1H)，0.91(t，3H)
Embodiment 33:
The evaluation of 5 '-'-deoxy-n-alkyl oxygen carbonyl-5-flurocytosine-5 '-carboxylic acid (compound of general formula 2a) external antitumour activity of derivative
For using the 5-FU antitumour activity of thing measurement the present invention 5 '-'-deoxy-n-alkyl oxygen carbonyl-5-flurocytosine-5 '-carboxylic acid (compound of general formula 2a) in contrast, measure cytotoxicity to the human cancer cell.The human cancer cell who uses is A549 (lung cancer), HCT15 (colorectal carcinoma), SK-OV-3 (ovarian cancer) and SK-MEL-2 (melanoma cancer).
With cancer cells in having the brooder of constant humidity, at 37 ℃ and 5%CO
2Under hatch, the RPMI medium with 10% fetal bovine serum is used for medium.Be to measure cytotoxicity, will be inoculated into 2-5 * 10 of 96 pond plates at the cancer cells of logarithm in mutually
4Each pond of individual cell, and hatched 24 hours, with 5-FU and 5 '-'-deoxy-n
4The progressively sample solution of dilution of-amyl group oxygen carbonyl-5-flurocytosine-5 '-carboxylic acid joined wherein and hatches subsequently 72 hours.The 5mg/ml MTT reaction soln that will be dissolved in 20 μ l of normal saline solution joins in each pond of hatching plate, hatched 4 hours, the first moon that produces is dissolved in methyl-sulphoxide for crystal, and the light absorption ratio of measuring each pond under the 540nm wavelength is to calculate the number of viable cell.When will there not being cell and have the pond light absorption ratio of medium to be set at 0%, will there be the pond light absorption ratio of sample to be set at 100% o'clock, have the IC that is called cancer therapy drug corresponding to the concentration of these results' 50% light absorption ratio
50Value.These the results are shown in Table 3.
| Cancerous cell line | ??A549 | ??SK-OV-3 | ???HCT15 | ???SK-MEL2 |
| 5-FU | ??0.26 | ????0.03 | ????0.11 | ????0.63 |
| Embodiment 25 (5 '-'-deoxy-ns 4-ethyl oxygen carbonyl-5- | ??0.49 | ????0.16 | ????0.47 | ????0.16 |
| Embodiment 28 (5 '-'-deoxy-ns 4-amyl group oxygen carbonyl-5- | ??0.17 | ????0.03 | ????0.12 | ????0.03 |
| Embodiment 30 (5 '-'-deoxy-ns 4-allyloxycarbonyl-5- | ??0.04 | ????0.008 | ????0.032 | ????0.008 |
| Embodiment 31 (5 '-'-deoxy-ns 4-propargyl oxygen carbonyl-5- | ??0.005 | ????0.005 | ????0.040 | ????0.007 |
Table 3
As shown in table 3, general formula 2 compounds according to the present invention are to the antitumour activity of the about 0.005-0.5 μ g/ml of each cancer cells demonstration, and comparing it with contrast is excellent.
Embodiment 34:
5 '-'-deoxy-n
4-(amyl group oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (R
3=amyl group, the compound of general formula 2a) the active evaluation of vivo antitumor
Has good anticancer active capecitabine (5 '-'-deoxy-n in disclosed 5 '-'-deoxy-n in European patent No.602454-alkyl oxygen carbonyl-5-flurocytosine derivative
4-(amyl group oxygen carbonyl)-5-flurocytosine (in general formula 1, R
a=amyl group, R
b=hydrogen)) as reference compound, from 5 '-'-deoxy-n of embodiment 3 acquisitions
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (general formula 2a) is measured the antitumour activity to mouse tumor cell line L1210 as sample.
The mouse of using is big BDF1 male mouses (19-20g) of 5 weeks, and these mouse adapted to for 1 week available from Charles RiverJapan with these mouse.With the breeding condition enactment of mouse is 24 ± 2 ℃ temperature and 50 ± 1 ℃ humidity.Purifying waste water of to being used to drink offers mouse and biweekly and with straw and one week of cage changes once.Use every group of two mouse to test.As tumor cell line, use L1210 mouse blood tumor cell system, with clone twice or three times of subculture in the Falcon culturing bottle, adopt inferior phosphorus buffered soln (pH7.2) washing, at microscopically quantitatively to produce 1 * 10
7The cell suspending liquid of/ml uses 1ml disposable sterilization syringe with 100 (1 * 10
6) ml cell suspending liquid belly gives mouse.After Transplanted cells, give 24 hours with drug oral.The concentration that gives for separately mouse capecitabine is 1.2,5.7,28.8,144 and 720mg/kg/100 μ l and be 1.2,5.8 and 28.8mg/kg/100 μ l for the concentration that gives of the general formula 2a of the present invention of mouse separately compound.Capecitabine is dissolved in methyl-sulphoxide and in 0.5% carboxymethyl cellulose, suspends, the compound of general formula 2a is dissolved in distilled water.Give mouse one Friday in inferior totally 3 weeks with sample, amount to 15 times, beginning in 24 hours after tumour cell gives.Antitumour activity is measured as increase life-span to contrast.The results are shown in Table 4.
| Compound | Dosage (mmol/kg/ days) | Average life keep fate (my god) | The life-span (%) that increases |
| Contrast | ????- | ????8.8 | ????- |
| Capecitabine | ????1.5 ????0.67 ????0.13 | ????12.5 ????9.6 ????9.4 | ????142.0 ????109.1 ????106.8 |
| Embodiment 28 (5 '-'-deoxy-ns 4-(amyl group oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid) | ????1.5 ????0.67 ????0.13 | ????16.8 ????11.3 ????9.1 | ????190.9 ????128.4 ????103.4 |
| ?5-FU | ????0.23 ????0.15 | ????16.5 ????14.3 | ????187.5 ????162.5 |
The active evaluation of table 4 vivo antitumor
Embodiment 35:
5 '-'-deoxy-n-active the evaluation of alkyl oxygen carbonyl-5-flurocytosine-5 '-carboxylic acid (compound of general formula 2a) derivative vivo antitumor
Has good anticancer active capecitabine (5 '-'-deoxy-n in disclosed 5 '-'-deoxy-n in European patent No.602454-alkyl oxygen carbonyl-5-flurocytosine derivative
4-(amyl group oxygen carbonyl)-5-flurocytosine (in general formula 1, R
a=amyl group, R
b=hydrogen)) as reference compound, from 5 '-'-deoxy-n of embodiment 3 acquisitions
4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid (general formula 2a) is measured the antitumour activity to mouse tumor cell line L1210 as sample.
The mouse of using is big BDF1 male mouses (19-20g) of 5 weeks, and these mouse adapted to for 1 week available from Charles RiverJapan with these mouse.With the breeding condition enactment of mouse is 24 ± 2 ℃ temperature and 50 ± 1 ℃ humidity.Purifying waste water of to being used to drink offers mouse and biweekly and with straw and one week of cage changes once.Use every group of two mouse to test.As tumor cell line, use L1210 mouse blood tumor cell system and, adopt inferior phosphorus buffered soln (pH7.2) washing clone twice or three times of subculture in the Falcon culturing bottle, at microscopically quantitatively to produce 1 * 10
7The cell suspending liquid of/ml uses 1ml disposable sterilization syringe with 100 (1 * 10
6) ml cell suspending liquid belly gives mouse.After Transplanted cells, give 24 hours with drug oral.Concentration for the capecitabine of separately mouse injection is 1.2,5.7,28.8,144 and 720mg/kg/100 μ l, and be 1.2,5.8 and 28.8mg/kg/100 μ l for the general formula 2a of the present invention of mouse separately compound concentrations.Capecitabine is dissolved in methyl-sulphoxide and in 0.5% carboxymethyl cellulose, suspends, the compound of general formula 2a is dissolved in distilled water.Give mouse one Friday in inferior totally 3 weeks with sample, amount to 15 times, beginning in 24 hours after tumour cell gives.Antitumour activity is measured as the life-span of increase.The results are shown in Table 5.
| Compound | Dosage (mg/kg/ days) | The average life fate (my god) | Life sustainment rate (%) |
| Contrast | ????- | ???17.8 | ????- |
| Capecitabine | ????720 ????144 ????28.8 ????5.8 ????1.2 | ???22.8 ???20.1 ???20.2 ???19.2 ???18.9 | ????30 ????15 ????14 ????8 ????6 |
| Embodiment 30 (5 '-'-deoxy-ns 4-(allyloxycarbonyl)-5-flurocytosine-5 '-carboxylic acid) | ????28.8 ????5.8 ????1.2 | ???25.7 ???24.8 ???22.1 | ????44 ????39 ????25 |
| Embodiment 31 (5 '-'-deoxy-ns 4-(propargyl oxygen carbonyl)-5-flurocytosine-5 '-carboxylic acid) | ????28.8 ????5.8 ? ????1.2 | ???21.9 ???20.6 ? ???20.1 | ????23 ????11 ? ????8 |
The active evaluation of table 5 vivo antitumor
Shown in table 4 and 5, general formula 2 compounds according to the present invention show excellent antitumour activity by animal testing.
Claims (7)
1. the 5-flurocytosine and the derivative thereof that have following general formula 2, pharmaceutical salts, or solvation material:
Wherein, R
1Be hydrogen, C
1-C
7Alkyl or C
1-C
7Alkynyl; R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
2-C
7Alkyl, alkenyl or alkynyl.
2. the 5-flurocytosine and the derivative thereof that have following general formula 3, pharmaceutical salts, or solvation material:
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
3. method for preparing 5-flurocytosine and the derivative thereof of general formula 2a comprises:
The compound of reaction expression 3a and alkali are with the compound of preparation general formula 3b;
The compound of oxidation general formula 3a,
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
4. method for preparing 5-flurocytosine and the derivative thereof of general formula 2b comprises the compound of esterification general formula 2a,
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
5. a method for preparing 5-flurocytosine and the derivative thereof of general formula 3b is included in the compound of reaction expression 4 under the alkali existence and the compound of general formula 5,
R
3OCOCI
(5)
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
6. the method for claim 5, wherein alkali is pyridine, triethylamine or diisopropylethylamine.
7. anti-cancer composition comprises the 5-flurocytosine and the derivative thereof of general formula 2 or 3,
Wherein, R
2Be the group of easy hydrolysis or the blocking group of under physiological condition, removing easily, preferred hydrogen or ethanoyl; R
3Be C
1-C
7Alkyl, alkenyl or alkynyl, R
4Be methylol or the methylol that contains blocking group.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020000046179A KR100730768B1 (en) | 2000-08-09 | 2000-08-09 | 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid and its derivatives, and process for preparing thereof |
| KR46179/2000 | 2000-08-09 | ||
| KR44193/2001 | 2001-07-23 | ||
| KR1020010044193A KR20030009649A (en) | 2001-07-23 | 2001-07-23 | N-alkynyloxycarbonyl-5-fluorocytosine derivatives, their preparation method, and anticancer agent comprising the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1446225A true CN1446225A (en) | 2003-10-01 |
Family
ID=26638291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01813741A Pending CN1446225A (en) | 2000-08-09 | 2001-08-08 | 5'-deoxy-N-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, method of preparing same, and anticancer composition comprising same as active ingredients |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1311524A2 (en) |
| JP (1) | JP2004505899A (en) |
| CN (1) | CN1446225A (en) |
| AU (1) | AU2001278804A1 (en) |
| WO (1) | WO2002011668A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103897004A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Synthesis method for capecitabine |
| CN101993464B (en) * | 2009-08-19 | 2014-07-23 | 成都弘达药业有限公司 | Preparation method of capecitabine |
| CN110831605A (en) * | 2017-04-26 | 2020-02-21 | 托马斯·I.·卡尔曼 | Multi-target nucleoside derivatives |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100216736A2 (en) * | 2006-07-21 | 2010-08-26 | Taiho Pharmaceutical Co., Ltd. | 2'-cyanopyrimidine nucleoside compound |
| SG11201810947PA (en) | 2016-06-28 | 2019-01-30 | Cellix Bio Private Ltd | Compositions and methods for the treatment of cancer |
| CA3108362A1 (en) * | 2018-08-03 | 2020-02-06 | Cellix Bio Private Limited | Compositions and methods for the treatment of cancer |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5968914A (en) * | 1987-10-28 | 1999-10-19 | Pro-Neuron, Inc. | Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides |
| US5276151A (en) * | 1990-02-01 | 1994-01-04 | Emory University | Method of synthesis of 1,3-dioxolane nucleosides |
| US5914331A (en) * | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
| US5204466A (en) * | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
-
2001
- 2001-08-08 WO PCT/KR2001/001351 patent/WO2002011668A2/en not_active Application Discontinuation
- 2001-08-08 EP EP01957021A patent/EP1311524A2/en not_active Withdrawn
- 2001-08-08 AU AU2001278804A patent/AU2001278804A1/en not_active Abandoned
- 2001-08-08 CN CN01813741A patent/CN1446225A/en active Pending
- 2001-08-08 JP JP2002517006A patent/JP2004505899A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101993464B (en) * | 2009-08-19 | 2014-07-23 | 成都弘达药业有限公司 | Preparation method of capecitabine |
| CN103897004A (en) * | 2012-12-27 | 2014-07-02 | 鲁南制药集团股份有限公司 | Synthesis method for capecitabine |
| CN103897004B (en) * | 2012-12-27 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of synthetic method of capecitabine |
| CN110831605A (en) * | 2017-04-26 | 2020-02-21 | 托马斯·I.·卡尔曼 | Multi-target nucleoside derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002011668A2 (en) | 2002-02-14 |
| WO2002011668A3 (en) | 2002-04-18 |
| EP1311524A2 (en) | 2003-05-21 |
| AU2001278804A1 (en) | 2002-02-18 |
| JP2004505899A (en) | 2004-02-26 |
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